(Circulation. 1999;100:75-81.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Prolonged Diastolic Time Fraction Protects Myocardial Perfusion When Coronary Blood Flow Is Reduced
From the Department of Medical Physics, Cardiovascular Research Institute Amsterdam, Academic Medical Center, University of Amsterdam (D.M., H.V., I.V., J.A.E.S.), and the Faculty of Design, Engineering and Production, Mechanical Engineering and Marine Technology, Laboratory for Measurement and Control, Delft University of Technology (J.D.), Netherlands; and the Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Okayama, Japan (F.K., M.G.).
Correspondence to Prof Dr Ir J.A.E. Spaan, Department of Medical Physics, Cardiovascular Research Institute Amsterdam, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail j.a.spaan{at}amc.uva.nl
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Abstract |
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Background—Because coronary blood flow is impeded during systole, the duration of diastole is an important determinant of myocardial perfusion. The aim of this study was to show that coronary flow modulates the duration of diastole at constant heart rate.
Methods and Results—In anesthetized, open-chest dogs, diastolic time fraction (DTF) increased significantly when coronary flow was reduced by lowering perfusion pressure from 100 to 70, 55, and 40 mm Hg. On average, DTF increased from 0.47±0.04 to 0.55±0.03 after a pressure step from 100 to 40 mm Hg in control, from 0.42±0.04 to 0.47±0.04 after administration of adenosine, and from 0.46±0.07 to 0.55±0.06 after L-NMMA (mean±SD, 6 dogs for control and adenosine, 4 dogs for L-NMMA, all P<0.05). Flow normalized to its value at full dilation and pressure of 90 mm Hg (375±25 mL/min) increased during the period of reduced pressure at 40 mm Hg; control, from 0.005±63 (2 seconds after pressure step) to 0.09±0.06 (15 seconds after pressure step); with adenosine, from 0.19±0.06 to 0.22±0.06; and with L-NMMA, from 0.013±0.007 to 0.12±0.02 (all P<0.05). The increase in DTF at low pressure may be explained by a decrease in interstitial volume at low pressure, which either decreases the preload of the myocytes or reduces the buffer capacity for ions determining repolarization, thereby causing an earlier onset of relaxation.
Conclusions—Because the largest increase in DTF occurs at pressures below the autoregulatory range when blood flow to the subendocardium is closely related to DTF, modulation of DTF by coronary blood flow can provide an important regulatory mechanism to match supply and demand of the myocardium when vasodilatory reserve is exhausted.
Key Words: diastole • metabolism • circulation • perfusion • contractility
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Introduction |
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With progression of atherosclerosis, the increase of resistance in the diseased coronary artery is compensated by reduction of tone in resistance vessels.1 2 However, when dilatory reserve is exhausted, coronary flow will depend strongly on the relative duration of diastole. This DTF is determined by heart rate3 4 and by factors that modulate systolic duration through modulation of myocyte contraction, such as endothelin-1, angiotensin II, and nitric oxide.5 6 7 8 In earlier studies, it has been demonstrated that occlusion of a major coronary artery results within seconds in shortening of the duration of systole.9 However, because heart rate was not controlled, this may be explained in part by an increase in heart rate.
We hypothesized that at constant heart rate, the effect of a decrease in perfusion pressure on coronary flow could be compensated by an increase in diastolic time fraction (DTF). This would be especially beneficial for subendocardial perfusion.3 An increase in diastolic duration may therefore be an important mechanism for matching coronary supply and demand of oxygen by simultaneously decreasing demand and increasing supply.
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Methods |
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Six dogs with a body weight of
20 kg were sedated with an
injection of ketamine (10 mg/kg IM) followed by an injection of
sodium pentobarbital (25 mg/kg IV) for anesthesia. Depth of
anesthesia was monitored by checking reflexes, and
additional anesthesia was given when necessary. After
tracheal intubation, dogs were ventilated with a mixture of room air
and oxygen by use of a jet ventilator at a rate sufficient to maintain
arterial oxygen and carbon dioxide tensions in the
physiological range (pH 7.35 to 7.45,
PCO2 25 to 40 mm Hg,
PO2 >70 mm Hg). When
necessary, sodium bicarbonate was given to avoid acidosis. A thin
polyethylene catheter was inserted into the left jugular vein for
administration of drugs. An 8F pigtail double-lumen manometer catheter
(microtip catheter transducer, model SPC-784A, Millar) was inserted,
with 1 of its sites of measurement placed in the left ventricle and the
second in the ascending aorta. A medial sternotomy and a thoracotomy
between the third and fourth ribs were performed, and the heart was
suspended in a pericardial cradle. Two pacing wires were sewn onto the
right atrial appendage. The sinus node was destroyed by injection of
40% formaldehyde, and the heart was paced at 100 to 120 bpm. After
administration of an initial intravenous dose of heparin
followed by continuous administration, the heart was perfused by means
of a perfusion system applying a stainless steel Gregg cannula ligated
into the left main coronary artery without disruption of
flow.10 Coronary blood flow was measured with an
in-line flow probe (Transonic 4F, T206). Perfusion pressure was
measured with a thin fluid-filled catheter at the cannula tip or with a
fluid-filled 24-gauge catheter in the first diagonal branch of the
LAD. All experiments were done in accordance with the guidelines on animal experiments of our institutions.
Protocol
Coronary arterial pressure was decreased
stepwise from 100 mm Hg to 70, 55, and 40 mm Hg, kept at
that level for 20 to 30 seconds, and then increased back to 100
mm Hg. The interventions were repeated with a stenosis on the
perfusion line and adjustment of reservoir pressure to obtain similar
average coronary pressures. This protocol was repeated 1) after
administration of adenosine (20 to 50 µg ·
kg-1 · min-1 IC)
such that reactive hyperemia resulting from 15 seconds of
occlusion disappeared and 2) after 20 minutes of administration of
NG-monomethyl-L-arginine
(L-NMMA) (4 µmol · kg-1 ·
min-1) (4 dogs) blocking nitric oxide
synthesis.11 Reduction of nitric oxide
synthesis was confirmed by comparing dilation to acetylcholine (1
µg/kg) before and after administration of L-NMMA in 3 dogs.
Determination of the Relative Duration of Diastole
Diastole was defined as the period when left
ventricular (LV) pressure was <25% of the range between
its minimal and maximal values and DTF as the quotient of the durations
of diastole and the entire heartbeat.
Statistics
The influences of adenosine, L-NMMA, and
coronary pressure on DTF were determined by ANOVA. If
significant differences were found, a pairwise multiple comparison
method (Bonferroni) and paired t tests were used to test the
differences between the individual groups.
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Results |
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Figure 1
shows a typical example of
the influence of perfusion pressure on DTF. After pressure decreased
stepwise from 100 to 35 mm Hg (top panel), flow decreased from 38
to -30 mL/min and then increased slowly to 12 mL/min (second and third
panels). Maximal LV pressure and aortic pressure remained constant
during the intervention (fourth panel). DTF (bottom panel) increased
from 0.45 to 0.57 during the period of reduced pressure. The increase
in DTF started 6 beats (3 seconds) after the decrease in pressure
and reached 50% of the maximal response after another 4 seconds. On
average, these numbers were 3.4±0.7 and 3.3±0.7 seconds (mean±SD),
respectively. The increase in DTF reversed rapidly during reactive
hyperemia when pressure was restored (Figure 2).
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Figure 3 shows LV pressure in control and
after administration of adenosine and L-NMMA in more detail.
The traces immediately after a pressure step from 100 to 40 mm Hg
(solid line) and 15 seconds later (dashed line) are superimposed, with
the rise in LV pressure used as reference. The early phase of
contraction and the rate of relaxation were comparable in both
situations. However, relaxation started earlier, 15 seconds after the
decrease in coronary pressure, resulting in prolonged duration
of diastole in all conditions.
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Figure 4 depicts different interventions
for 1 dog. Steady-state DTF is plotted as a function of pressure and as
a function of flow. DTF increased with decreasing coronary
pressure with or without stenosis. With adenosine, DTF
is lower at all pressures, and the onset of the increase in DTF on a
decrease in pressure was delayed (4.8±0.7 seconds after
adenosine compared with 3.4±0.7 seconds in controls). The
relation between pressure and DTF in the presence of L-NMMA was not
different from that in controls. The reduction of DTF by
adenosine is consistent with the DTF-flow relationships
in the presence of tone (Figure 4, right).
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, dashed line) decreases DTF at all pressures
compared with control (
) and L-NMMA (
) (fitted with solid line).
Right, Relation between flow and DTF obtained in control, with L-NMMA,
and with adenosine in absence and presence of a
stenosis on perfusion line. This relation is steepest at low
flows and flattens at high flows (solid line indicates fit of
relation).
Figure 5 depicts the average steady-state
DTF for the different interventions as a function of flow normalized
with respect to flow at full vasodilation and pressure of 90
mm Hg (average for 6 dogs in control and with adenosine, 4
dogs with L-NMMA). DTF increased with decreasing flow in a nonlinear
way. At normalized flows >0.375 (150 mL/min), DTF was not influenced
by changes in flow, whereas DTF is strongly related to flow below this
threshold. Furthermore, the low-flow data obtained with
adenosine fit within the relation obtained in controls and
after administration L-NMMA.
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Both DTF and flow increased with time after an initial period of 3
seconds, excluding capacitive effects. On average, DTF increased from
0.47±0.04 to 0.55±0.03 after a pressure step from 100 to 40
mm Hg in control, from 0.42±0.04 to 0.47±0.04 with
adenosine, and from 0.46±0.07 to 0.55±0.06 with L-NMMA (all
mean±SD, 6 dogs on control and adenosine, 4 dogs for L-NMMA,
all P<0.05). Normalized flow also increased during the
period of reduced pressure at 40 mm Hg: from 0.005±0.063 (3
seconds after pressure step) to 0.09±0.06 (15 seconds after pressure
step) in controls, from 0.19±0.06 to 0.22±0.06 with
adenosine, and from 0.013±0.007 to 0.12±0.02 with L-NMMA (all
P<0.05). With adenosine, the increase in flow must
be due to the increase in DTF. In control and after L-NMMA,
vasodilation contributes to the increase in flow as well.
The relations between DTF and flow for the different conditions in 1
representative experiment are depicted in Figure 6 (see Table 1 for average data). The course of
events is as follows: Flow decreases (measured after the first 3
seconds) after a drop in coronary pressure, as indicated by the
vertical dashed lines in Figure 6. The data points and regression lines
give the simultaneous increase of DTF and flow during the
15-second equilibration time. These relations are steeper in control
than after adenosine, because of autoregulation in the former
condition. With a pressure step to 70 mm Hg, there is almost no
increase in DTF; hence, the increase in flow must be due to
vasodilation. At 35 mm Hg, however, the slope of the relation
between DTF and flow in control is only slightly steeper than that with
adenosine, indicating a relatively small contribution of
vasodilation to the increase in flow at low pressure.
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Eventually, the flow and DTF reach a new steady state,
represented by the continuous curve in Figure 6
, which is the best fit for this condition in this experiment (compare
with steady-state relation between DTF and flow in Figure 4, right). Hence, because of the hyperbolic relation between DTF and flow,
there is little change in DTF in the high flow range of Figures 4 (right) and 5. This interpretation is also
consistent with the rather constant DTF at pressures >70
mm Hg in the presence of tone, as shown in Figure 4, left,
because flow is rather independent of pressure in that pressure
range.
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Discussion |
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In this study, we elaborated on earlier observations that the duration of systole may shorten under ischemic conditions.9 12 We clearly demonstrate that such shortening occurs even when heart rate is controlled. We reported our results as DTF because this parameter is closely related to subendocardial perfusion.3 4 We found that DTF is unaffected by changes in coronary flow above
150 mL/min,
which is somewhat higher than the physiological
control flow in our experiments with autoregulation intact. The
increase in DTF was related to the reduction in flow below this
threshold, ie, flows within or below the autoregulatory range. We
further demonstrated that this flow-related phenomenon is not based on
production of NO. Because increases in DTF occur mainly when
vasodilatory reserve is exhausted, DTF-related increases in myocardial
perfusion may benefit myocardial oxygen supply when perfusion is
compromised.
Discussion of Methods
We defined diastole as the period when LV pressure was
<25% of the range between its minimal and maximal values. Estimating
DTF as the period between minimal and maximal LV dP/dt or as the period
between minimal LV dP/dt and opening of the aortic valve for 1 pressure
step in each dog3 4 9 12 resulted in values of DTF that
were 0.11±0.02 and 0.10±0.03 higher than our initial estimate (both
P<0.05). However, the changes in DTF on a change in
pressure were similar (P=0.85 and P=0.40).
In earlier studies reporting on shortening of systole, a coronary branch was occluded.9 12 These experiments demonstrate a reduced ventricular relaxation rate, which can be explained by an inhomogeneous onset of relaxation. Minimal LV dP/dt, as an index of relaxation rate, did not change during our interventions with total perfusion.
The same increase in DTF was found at different rates of pressure decrease (from stepwise to slow ramps of 3 mm Hg/s). The increase in DTF on a decrease in flow is not species dependent, because we found the same in goats.
Possible Mechanisms of Increasing DTF
Ischemia may occur at low perfusion pressure. Fifteen
beats after the onset of underperfusion, phosphocreatine and ATP
contents decrease in the subendocardium, without a change in lactate
content.13 This may open the ATP-dependent
K+ channels, which can result in an earlier onset
of relaxation. However, glibenclamide (220 mL, 1 mg/mL) administered in
similar experiments performed in goats did not influence the change in
DTF during total coronary occlusion (data not shown), making a
role of the ATP-dependent K+ channels
unlikely.
Some other observations make it unlikely that DTF increased as a result
of a possible shortage of oxygen: at a perfusion pressure of 100
mm Hg, DTF decreased when flow was increased by adenosine,
implying that DTF can also vary in a nonischemic heart.
Moreover, injections of anoxic saline in similar experiments always
resulted in a decrease in DTF (14 injections in 5 dogs, typical example
in Figure 7) while decreasing the oxygen
content of blood. Furthermore, DTF increases only in the first 15
seconds after the pressure reduction and is stable thereafter, whereas
a possible degree of ischemia will develop further in time,
depending on the amount of flow reduction.
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Table 2 lists a series of substances
produced by endothelial cells that may influence
myocyte function.5 6 7 14 15 16 17 18 19 20 21 22 23 From this list, only
the production of nitric oxide can change fast enough to
explain the increase in DTF. However, in the experiments in which
nitric oxide synthase was blocked by administration of L-NMMA, the
changes in DTF were similar to those in control at all pressures.
Hence, no known paracrine pathway can be responsible for the increase
in DTF at decreased pressure.
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DTF changes induced by underperfusion are compatible with a dominant role of interstitial volume that may alter the contraction duration of the myocytes either through influencing the sarcomere length24 25 or through changes in extracellular concentration of ions involved in repolarization.26 Interstitial volume variations are to be expected with changes in flow, both in control and with adenosine, by variation of capillary pressure27 but also with saline infusion by decreasing plasma oncotic pressure. Also, the time course of DTF variation, being slower than intravascular volume variations,28 is consistent with this hypothesis.29
Interpretation of Findings
In a heart with normal coronary regulation, local flow is
adapted to match the metabolic needs of the
myocardium by vasodilation. However, with a severe
stenosis in the coronary arteries, the possibility for
further dilation of the resistance vessels by
physiological stimuli is exhausted, although
further pharmacological dilatation is possible.30 31 32 33 In
these circumstances, coronary flow is determined by mechanical
forces, such as compression of intramyocardial vessels by the
surrounding myocardium during contraction. An increase in
DTF will be beneficial to myocardial perfusion because the time that
intramyocardial vessels are compressed decreases. Hence, lengthening of
DTF may be important at some stage of transition from normal to
ischemia, resulting in delayed occurrence of ischemia.
This stage may be of either short or long duration, depending on the
rate of development of the disease.
With a coronary stenosis, the difference between diastolic and systolic flow becomes less, but coronary pressure becomes more pulsatile.10 Therefore, the relative contribution of systolic flow to total flow may increase,1 34 especially if the stenosis is compliant.35 Hence, there are 3 factors that might have contributed to the increase in total flow at low pressure: the increase in DTF, vasodilation, and an increased contribution of systolic flow.
The effect of DTF on flow is clear when vasomotor tone is abolished and
is larger at lower flow and pressure levels. The contribution of
vasodilation to the increase in flow can be estimated as the difference
between the slopes of the DTF-flow relations in control and with
adenosine, as discussed above in relation to Figure 6.
This figure also demonstrates that in the presence of autoregulation,
the effect of DTF becomes more important at lower perfusion
pressure.
Because vasomotor tone changes are dominant, when present, the
effect of DTF on the contribution of systolic flow to total
flow can be studied only in the presence of adenosine. At
constant pressure, the influence of DTF on minimal (systolic)
and maximal (diastolic) flow was similar (Table 1).
An increase in diastolic time, at the expense of
systolic time, reduces the time for squeezing blood out of the
vessels and increases the time for volume recovery, thereby keeping the
intramural vessels at a lower resistance. This may affect both
systolic and diastolic flow.
When discussing phasic coronary flow, one has to be aware of capacitive effects. The perfusion system did not add any significant compliance, because the in-line flow probe was connected closely to a steel cannula. Coronary arterial flow is phasic, and systolic flow can be retrograde because of the intramyocardial pump action on the intramural compliance.10 However, the relations between DTF and systolic and diastolic flow were measured at constant coronary pressure, minimizing these epicardial capacitive effects that could have changed the phasic flow patterns. Obviously, the phasic flow patterns measured at the level of the larger arteries is different from those of the smaller vessels and veins and may be different at the subendocardium and subepicardium. However, such differences seem not to influence the DTF–arterial flow relationship.
In the presence of a rigid stenosis, as in our case, the
difference between systolic and diastolic flow is
minimized. Therefore, the effects of DTF on systolic and
diastolic flow are similar. It should be noted, however,
that when coronary resistance changes with either DTF or
vasodilation in the presence of a stenosis, this affects not
only flow but also the pressure drop over the stenosis. This is
the reason that DTF-flow slopes are not provided in Table 1 for
the stenosis case.
Because flow and DTF are changing continuously after a pressure step, the microsphere technique is not suitable for measuring subendocardial flow. However, a 1% DTF increase by lowering heart rate increases subendocardial flow by 2.6% to 6.0% but has no effect on subepicardial flow.3 4 These findings tally well with the increase of 2.6% total flow with 1% increase in DTF in our experiments.
Shortening of the duration of contraction may also contribute to the decreased oxygen consumption found on a decrease in coronary arterial pressure.36 Hence, the effect of increased DTF may affect the oxygen supply-demand ratio both by increasing supply and decreasing demand.
Conclusions
At a constant heart rate, a decrease in coronary perfusion
results in an increase in DTF, which cannot be explained by release of
a known cardioactive factor in response to hypoxia. The
hypothesis that DTF changes in relation to changes in
interstitial volume is worth pursuing. However, further
studies are necessary to definitively determine the relative importance
of ischemia versus change in interstitial volume.
Because DTF is an important determinant of subendocardial flow, it may
provide a potential protective mechanism against endocardial
ischemia when coronary perfusion is impaired.
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Acknowledgments |
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Financial support from the Netherlands Heart Foundation (grant 92.128) and the Netherlands Organization for Scientific Research (NWO, travel grant R90-160) is gratefully acknowledged.
Received December 10, 1998; revision received March 25, 1999; accepted March 30, 1999.
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D. S. Fokkema, J. W. G. E. VanTeeffelen, S. Dekker, I. Vergroesen, J. B. Reitsma, and J. A. E. Spaan Diastolic time fraction as a determinant of subendocardial perfusion Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2450 - H2456. [Abstract] [Full Text] [PDF]
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C. S. Chung, M. Karamanoglu, and S. J. Kovacs Duration of diastole and its phases as a function of heart rate during supine bicycle exercise Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2003 - H2008. [Abstract] [Full Text] [PDF]
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H. Sato, H. Yaoita, K. Maehara, and Y. Maruyama Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H359 - H368. [Abstract] [Full Text] [PDF]
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C. Gonzalez-Castillo, R. Rubio, and T. Zenteno-Savin Coronary flow-induced inotropism is modulated by binding of dextrans to the endothelial luminal surface Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1348 - H1357. [Abstract] [Full Text] [PDF]
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R. R. Lamberts, M. H. P. van Rijen, P. Sipkema, P. Fransen, S. U. Sys, and N. Westerhof Coronary perfusion and muscle lengthening increase cardiac contraction: different stretch-triggered mechanisms Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1515 - H1522. [Abstract] [Full Text] [PDF]
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D. Merkus, I. Vergroesen, O. Hiramatsu, H. Tachibana, H. Nakamoto, E. Toyota, M. Goto, Y. Ogasawara, J. A. E. Spaan, and F. Kajiya Stenosis differentially affects subendocardial and subepicardial arterioles in vivo Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1674 - H1682. [Abstract] [Full Text] [PDF]
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R. R. Lamberts, M. H. P. van Rijen, P. Sipkema, P. Fransen, S. U. Sys, and N. Westerhof Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1334 - H1340. [Abstract] [Full Text] [PDF]
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A. J. M. Cornelissen, J. Dankelman, E. VanBavel, and J. A. E. Spaan Balance between myogenic, flow-dependent, and metabolic flow control in coronary arterial tree: a model study Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2224 - H2237. [Abstract] [Full Text] [PDF]
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